PROJECT SUMMARY/ABSTRACT Although dementia has a global impact, efforts to address ensuing challenges have come mostly from high- income countries (HICs). Whereas the prevalence and incidence of dementia appear to be stable or declining in such countries, an alarmingly opposite tendency typifies South American countries (SAC). This scenario proves even more challenging due to region-specific traits. First, the particular genetic and environmental backgrounds of SAC limit the generalizability of key findings from HICs. Moreover, the greater genetic diversity and impact of socioeconomic status (SES) of SAC remain markedly understudied. Of note, this is true of the four largest SAC (Brazil, Argentina, Colombia, and Peru), representing over 75% of the region?s population. In addition, SAC face a dearth of innovative, harmonized, and cross-regional studies on two of their most prevalent neurodegenerative disorders: Alzheimer?s disease (AD) and frontotemporal dementia (FTD). It is thus critical for SAC to join ongoing international efforts and develop a gold-standard approach for detecting disease-specific alterations in a context of methodological, genetic, and socioeconomic heterogeneity. Against this background, our long-term goal is to identify the unique genetic and SES factors that drive AD and FTD presentation in SAC relative to the US. To this end, we will establish a cohort to test large samples from the four abovementioned SAC, as well as the US (totaling > 3000 participants, including 1500 controls, 750 AD patients, and 750 FTD patients). We will combine standardized clinical assessments with innovative analytical techniques including multimodal machine learning to account for heterogeneity in these diverse populations. By combining standardized genetic, neuroimaging, and behavioral (SES-cognitive) measures, we will test the underlying hypothesis that there are unique risk factors for AD and FTD in SAC which do not prove significant in US populations. More particularly, we will aim to (a) establish genetic risk to AD and FTD in diverse SAC cohorts; (b) test whether patients from SAC and the US can be discriminated after accounting for how SES affects cognitive and brain imaging signatures; and (c) determine genetic, cognitive, cerebral, and socioeconomic factors that discriminate among SAC vs. US patients. Positive impacts of this work include a better understanding of the genetic and socioeconomic factors driving neurocognitive manifestations of dementia, and the identification of novel genetic targets for risk reduction and disease prevention in SAC. Our large multimodal, cross-sectional study will enable clinical assessment of understudied patient groups, extend and harmonize existing data sets, and prompt the development of novel measures and multimodal machine learning protocols. More generally, by establishing a collaborative framework which capitalizes on unique regional populations, our proposal can consolidate a SAC-based platform for future translational research and assessment.